Sedative compounds



Patented Aug. 14, 1934 museums PAT N OFFKIE SEDATIVE COMPOUNDS ErnestHfvolwiler, Highland Bark, and yDo nalee.

' L. Tabern, Lake Bluff, Ill., assignors toAbbott Laboratories, NorthChicago, 111., a corporation of Illinois No Drawing.

9 Claims.

It has. longbeen known that anumberof alkyl substituted amides andureides of the aliphatic series produce sedation and sleep. Most ofthese compounds, however, are relatively weak in their 5 sedative andsleep-producing actions, being, in

general, considerably lessefiicient than the corresponding barbituricacid derivatives.

We have now found, however, that the therapeutic activity of this typeof compounds may be .10 markedly enhanced by the substitution of higheralkyl groups in the compounds, and thatithe new substances have asurprisingly low toxicity.

These compounds may be represented by the general formula:

X R-ll-C' ONRR" where R. represents asatur'ated alkyl group, R

represents a secondary 'alliyl group containing more than 3-carbonatoms, X represents hydrogen or a halogen atom, R represents hydrogen oran aliphatic hydrocarbon group, and R represents hydrogen, an aliphatichydrocarbon group, the group CONI-Iz, or the group C-ONI-ICOCHa.

The amides of this class; of compounds having the general formula may beprepared by'treating the required acid chloride with ammoniaor a primaryor secondary amine of the aliphatic hydrocarbon series.

The corresponding acetyl urea compounds having the general formula maybe prepared by heating the necessary acetyl urea compound with acetylchloride and acetic anhydride, in the presence of zinc chloride.

Application November 9, 193 1 Serial No. 574,038

Example 1.E thyl (l-methyl butyl) acetamide Ethyl (l methyl butyl)aceticacid isprepared. by the hydrolysis of ethyl (l-methyl butyl) ma-Ionic ester byrefluxing with an equalweight. of potassiumhydroxide indilute alcohol. Following the hydrolysis, the alcohol is removed bydistilla tion, the reaction mixture is neutralized with hydrochloricacid, the ethyl (1-methy1 butyl) malonic acid extracted with benzene,the solvent removed by distillation; and finally the ethyl (1- methylbutyl) malonic acid heated and distilled to eliminate carbon dioxiderThe ethyl (l-methyl butyl) acetic acid so obtained boils at 225 to 230Q. It is converted by thionyl chloride at room temperature or slightlyabove'into the corresponding acetyl chloride, which boils at 103 to 108C. at mm. To prepare ethyl (l-methyl butyl) acetamide, aqueousconcentratedammonia solution is cooled and 'further'saturated'withammoniar While being held at below 10 0., the above acid chloride isslowly dropped in, immediate reaction taking place. After several hoursstirring, the mass is filtered,- dissolved in alcohol and poured withstirringinto cold water. The ethyl (l-methyl butyl) acetamide soobtained melts at 97 to 98 C.

Example 2.Etliyli(1-methyl butyl) acetyl urea Thirty 'grams of ethyl(l-methyl butyl) acetyl chloride, together with 25 grams of urea, isplaced in a flask equipped with a stirrer and condenser and the mixtureis heated to 130C. Considerable heat is evolved and the lower layerturns solid. It is held at 80 -to 100 C. for'two hours and cooled toroomtemperature. The product is washed with dilute sodium hydroxide andrecrystallized from dilute alcohol. 'The product melts at 130 to133-C.The same product may also be prepared by hydrolysis of the sodium saltof ethyl (l-methyl butyl) barbituric acid by heating in a sealed tubewith water at 100 C. for several days.

Example 3.--Ethyl alpha Drama (1 -methyl butyl) acetyl urea To ethyl(l-methyl butyl) acetyl chloride at 100 C., there is gradually added onemolecular equivalent of bromine. The reaction is very rapid. The productis distilled. It boils at 135 to 150 C. at mm. It is condensed withammonia to produce the corresponding amide or with urea to produce theureide as described in Examples 1 and 2.

Example 4.-Acetyl ethyl 1 methyl butyl) acetyl urea A mixture isprepared of ten grams acetyl chlo-- ride, twenty-five grams aceticanhydride, fifteen grams zinc chloride, and ten grams ethyl-(1- methylbutyD- acetamid. The temperature rises to about 50 C. and all the amidedissolves. Wa-

ter and ice are added, the mixture extracted with ether, the ethersolution washed with sodium hydroxide solution, dried with anhydroussodium sulfate, and the ether removed. The acetyl ethyl (l-methyl butyl)acetyl urea so obtainedis an oil. By the above methods, the followingcompounds with their melting points have been prepared: 7

Melting Compound point (l-Methyl butyl) acctyl urea 180 C Ethyl(l-methyl butvll acetamid. 97-98 Ethyl (lqnethyl butyl) acetyl'urea.Alphc-bromo- (Lmethyl but-yl) acetamii Alpha-bromo-il-methyl butyl)methyl ac Ethyl secondorybutyl acetyl urea n-Butyl (l-mctliyl butyl)acetyl urea n-Butyl (l-methyl butyl) acetarnid Acetyl ethyl-(l-methylbutyl) acetyl urea X R(|3-C O N HR in which R represents a saturatedalkylgroup, R represents a secondary alkyl group containing 4 or 5carbon atoms, Xrepresents hydrogen or a halogen atom, and R" representshydrogen or an aliphatic hydrocarbon group.

3. A compound'of the general structure:'

in which R represents a saturated-alkyl group, R represents a secondaryalkyl group containing 'in which R'represents a saturated alkyl group,

4 or 5 carbon atoms, X represents hydrogen or a halogen atom, and R""represents hydrogen or the group COCHs.

4. A compound of the general structure:

and X represents hydrogen or a halogen atom.

5. A compound of the general structure inwhich R is an alkyl group andR' represents hydrogen or the group CONHzorCONHCOCHa,

6. A compound 01' the general structure:

. H R-('JCONH| ciauomomou V OH. in which R is an alkyl group. m5

7. A compound having the structure;

in which R represents hydrogen or the group CONH2 or CONHCOCHa. 1

8. The compound ethyl-(lemethyl butyl acetyl urea, having the structure:

9. The compound ethyl l-methyl butyl acetamide having the structure;

omcrncn, ,u

ERNEST H. 'voLWILER. DONALEE, L. TABERN.

